Dr. Croce has been investigating the genes and the genetic mechanisms involved in the pathogenesis of human cancer, focusing on the early genetic changes. He discovered the juxtaposition of the human immunoglobulin genes and the MYC oncogene, the deregulation of MYC in Burkitt lymphoma, and cloned and characterized the BCL2 gene involved in follicular lymphoma.

Croce's group focuses on the initiating events responsible for the pathogenesis of human hematopoietic malignancies and on the early events involved in the pathogenesis of human cancer; head and neck cancer and gastrointestinal cancer. These studies have led to the identification of several genes that play an important role in the initiation of several important human neoplastic diseases:

ALL1, that is involved in human acute leukemias, including acute lymphoblastic leukemia, acute myelogenous leukemia, acute myelomonocytic leukemia and acute monocytic leukemia. Dr. Croce's group has also shown that ALL1 can fuse with itself (this mechanism is called ‘self fusion') leading to acute myelogenous leukemia. They have also identified several gene targets of ALL1, including a gene named ARP, the expression of which is lost in acute leukemias carrying chromosome translocations involving the ALL1 locus at 11q23.

TCL1, that is involved in chronic T-cell leukemia and adult T-cell leukemia.

FHIT, that is involved early on in the pathogenesis of lung cancer, nasopharyngeal and esophageal cancer, gastrointestinal cancer, breast cancer, head and neck cancer, and cervical cancer. This gene contains the most common fragile site of the human genome, FRA3B, that appears to be the target for genetic rearrangements caused by a variety of environmental carcinogens.

Dr. Croce and his research group have also continued studies on the role of TAL1/ SCL/TCL5 in the pathogenesis of human leukemias and in hematopoietic differentiation. They have developed a TAL1 transgenic mouse model, in which overexpression of the gene leads to acute leukemia or high grade lymphoma.